Axial chirality and affinity at the GABAA receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

The pyrimido[1,2-a][1,4]benzodiazepines (1a–c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2′-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a–c was revealed to be the eutomer in GABAA receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC50 value of 1.5 nM.

Figure optionsDownload as PowerPoint slide